This project seeks to develop the IMMSIM model of host responses to its full potential as a supporting and predictive tool for infection research. This effort is carried out by a multidisciplinary cooperation of mathematical modelers and immunologists working with viruses of the pox and arenavirus families, which both belong to the A category, and hence the simulator may become of interest in the frame of the current NIAID Biodefense Research protocols. Two issues are central for the understanding of anti-virus responses: the multi-threshold mechanism of T cell activation, and the changeable clonal hierarchy of T cell memory. In both areas breakthroughs have been made in the last year, with important consequences for protection strategies. With the new T cell features incorporated, the model shall be tested for reliability in reproducing bench results and hypotheses, and its predictions shall be challenged by means of ad hoc in vivo or in vitro experiments. The study will focus on: a) the nature of clonal dominance and clonal attrition, asking whether the signal for induced apoptosis is originated by competition of local resources (antigen, lymphokines) or by global population constraints; b) the reasons for the apparent asymmetry of the effects of crossreactions, when two viral infections are enacted in opposite order; and c) the possible advantage of using heterologous (but not B-crossreacting) instead of homologous vaccines, in order to avoid neutralization by circulating antibodies and thus to reach a more predictable protection.